💊 Chemical information

Chemical formula: C17H12Cl2N4 = 343.2.

CAS — 28911-01-5.

ATC — N05CD05.

ATC Vet — QN05CD05.

Pharmacopoeias.

In Chin. and US.

USP 31

(Triazolam). A white to off-white, practically odourless, crystalline powder. Practically insoluble in water and in ether; soluble 1 in 1000 of alcohol, 1 in 25 of chloroform, and 1 in 600 of 0.1N hydrochloric acid.

Effects on mental function.

The effects of triazolam on mental function have been controversial since van der Kroef first described in 1979 a range of symptoms including anxiety, amnesia, depersonalisation and derealisation, depression, paranoia, and severe suicidal tendencies that he had seen in 25 patients and attributed to triazolam.1 This led to suspension of triazolam in the Netherlands (re-approved in 1990) and removal of the 1-mg tablet from other markets. Continued reporting of similar symptoms of cognitive impairment with triazolam resulted in withdrawal of the 500-microgram dosage form in several countries in 1987 and 1988 and in a gradual reduction of recommended dosage from 1 mg at night down to 125 to 250 micrograms at night. Triazolam was withdrawn from the UK2 and some other markets in 1991. Opinion still remains divided over the adverse effects of triazolam, the main issues being its propensity to cause adverse effects relative to other benzodiazepines and whether its risk-benefit ratio is acceptable to justify its continued use.3,4 Others5 have reviewed spontaneous adverse effects reported to the FDA in the USA for triazolam, temazepam, and flurazepam. Daytime sedation was noted with all three, but triazolam caused more agitation, confusion, hallucinations, and amnesia. Such effects occurred frequently with the 250-microgram dose as well as with the 500-microgram dose. Similar results were obtained after analysis of reports for triazolam and temazepam in the first 7 years of marketing, although the possibility that selection factors were producing higher reporting rates for triazolam could not be entirely excluded.6 A study7 gave triazolam 500 micrograms, lormetazepam 2 mg, or placebo, to groups of 40 patients for 25 nights and observed the greatest frequency of daytime anxiety, panic, derealisation, and paranoia with triazolam. Another8 found a greater total number of reports of memory impairment or amnesia after nightly doses of triazolam 500 micrograms compared with temazepam 30 mg. Triazolam also impaired delayed, but not immediate, memory recall. Similar cases of memory impairment occurring with triazolam at doses of 125 and 250 micrograms have reportedly been submitted to the UK CSM.2 The emergence of daytime symptoms after more than a few days’ treatment with triazolam could be attributed to rebound or withdrawal phenomena occurring as a result of rapid elimination of the drug. As regards the risk-benefit ratio of triazolam some workers have questioned the hypnotic efficacy of the drug at a dose of 250 micrograms and consider that reduction of the dose has decreased efficacy more than adverse effects.3 In defence of triazolam, the FDA and the manufacturers (Upjohn) have considered epidemiological studies which, unlike the FDA spontaneous reporting scheme, have been unable to demonstrate a substantial difference in its adverse effects compared with other benzodiazepines except, perhaps, in the incidence of amnesia.9 Retrospective studies10,11 claiming similar findings have been the subject of criticism.12-14 Other workers have cited studies indicating benefit of triazolam 250 micrograms for the treatment of insomnia.15 A review by the US Institute of Medicine found that triazolam was safe when given in a dose of 250 micrograms daily for 7 to 10 days but called for studies of lower doses and of long-term use.16

💊 Precautions

Hepatic impairment.

Cirrhosis decreased the apparent oral clearance of triazolam to an extent depending on the severity of the liver disease.1 An initial dose of 125 micrograms was suggested for patients with severe liver dysfunction. It was suggested that the relative lack of effect that mild to moderate cirrhosis had on the metabolism of oral triazolam might be due to some first-pass metabolism occurring in the intestinal wall.2

Renal impairment.

Peak plasma-triazolam concentrations were lower in 11 dialysis patients compared with 11 controls.1 It was postulated that a relatively high basal gastric acid secretion in dialysis patients could result in hydrolysis and opening of the ring structure of triazolam effectively reducing its systemic avail ability. Giving an antacid could reverse this effect. Renal failure had no other effect on the pharmacokinetics of triazolam which could probably be given in usual doses.

💊 Interactions

💊 Pharmacokinetics

Triazolam is rapidly and nearly completely absorbed from the gastrointestinal tract, peak plasma concentrations being achieved within 2 hours of an oral dose. Triazolam has a plasma elimination half-life ranging from 1.5 to 5.5 hours. It is reported to be about 89% bound to plasma proteins. Hydroxylation of triazolam in the liver is mediated by the cytochrome P450 isoenzyme CYP3A4. Triazolam is excreted in the urine mainly in the form of its conjugated metabolites with only small amounts appearing unchanged.

💊 Uses and Administration

Triazolam is a short-acting benzodiazepine with general properties similar to those of diazepam. It is used as a hypnotic in the short-term management of insomnia in oral doses of 125 to 250 micrograms at night for no more than 2 weeks; doses of up to 500 micrograms at night have been used for resistant cases but these may be associated with an increased risk of severe adverse effects (see Effects on Mental Function, above). Initial doses of 125 micrograms at night have been suggested for elderly or debilitated subjects, increased up to a maximum of 250 micrograms only if necessary.